Dysregulation of LIMK-1/Cofilin-1 pathway: A possible basis for alteration of neuronal morphology in experimental cerebral malaria

ABSTRACT

Objective: Loss of cognition even after survival is the salient feature of cerebral malaria (CM). Currently, the fate of neuronal morphology is not studied at the ultra-structural level in CM. Recent studies suggest that maintenance of neuronal morphology and dendritic spine density (actin dynamics in particular) are essential for proper cognitive functions. LIMK-1/Cofilin-1signaling pathway is known to involve in the maintenance of actin dynamics through regulation of cofilin-1, in executing learning and memory functions.

Methods: Using experimental mouse model, we analyzed the behavioural parameters of CM, asymptomatic mice by performing Rapid Murine Coma Behaviour Scale experiment (RMCBS). We performed Golgi-Cox staining to assess neuronal morphology, dendritic spine density and arborization in the brain cortex subjected to Plasmodium berghei ANKA infection compared to asymptomatic, anemic and control groups. We studied the neural gene expression pattern of LIMK-1, cofilin-1 and β-actin in all the experimental groups by semi-quantitative, quantitative PCR followed by immunoblotting and immunofluorescence.

Results: We observed significant loss of dendritic spine density, abnormal spine morphology, reduced dendritic arborization; extensive dendritic varicosities in the cortical neurons of CM infected brain. Further, these observations correlated with diminished protein levels of LIMK-1, cofilin-1, phospho-cofilin-1 and β-actin in the whole brain lysates as well as formation of actin-cofilin rods in the brain sections of mice symptomatic to CM.

Interpretation: Overall, our findings suggest that the altered neuronal morphology and dysregulation of LIMK-1/cofilin-1 pathway could affect the cognitive outcome after experimental CM. Therefore, this study could help to establish newer therapeutic strategies aiming long-term cognitive impairment after CM. This article is protected by copyright. All rights reserved.

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